title: In silico design of tubulin-targeted antimitotic peptides.
abstract: Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein-protein interface allows us to identify the amino acids responsible for tubulin-tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.
authors.affiliation: Dipartimento di Chimica Fisica ed Elettrochimica, Università degli Studi di Milano, Via Golgi 19, Milano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pieraccini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Saladino
authors.forename: Graziella
authors.initials: G
authors.lastname: Cappelletti
authors.forename: Daniele
authors.initials: D
authors.lastname: Cartelli
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Francescato
authors.forename: Giovanna
authors.initials: G
authors.lastname: Speranza
authors.forename: Paolo
authors.initials: P
authors.lastname: Manitto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000595:Amino Acid Sequence; D050256:Antimitotic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D050256:Antimitotic Agents; D009842:Oligopeptides; D014404:Tubulin